Our section has developed protocols for the treatment and study of thoracic malignancies including mesothelioma, metastatic disease to the lungs, and esophageal cancer. The primary protocols for mesothelioma have been using intraoperative photodynamic therapy at the time of maximal resection of disease, which led to a completed Phase I trial which defined the maximum tolerated dose of PDT at the time of thoracotomy to be 30 Joules/cm2 after a 24 hour dosing interval of the sensitizer Photofrin II. We have developed an immunochemotherapy regimen in a Phase II trial using interferon, cisplatinum and tamoxifen (CIT) for pleural mesothelioma with a 20% response rate as detected by three dimensional volumetric analysis of computerized tomographic responses. The CIT regimen has also been used as an adjuvant treatment in ten patients after resection of their mesothelioma. A Phase III trial comparing surgery, PDT, and CIT vs surgery and CIT has been developed and is accruing patients. Mesothelioma tissue from these patients has been used to develop 9 new cell lines, which are being used for molecular biologic analysis of the disease including p53 status, 3p deletional information, Wilms tumor suppressor gene status, growth factor production including PDGF, IGF-2, TGFalpha, LIF, etc, as well as analysis for SV4O incorporation. We are attempting to incorporate the thymidine kinase gene into the cell lines for development of future treatment strategies. In vitro chemo, and in vitro radiation sensitivity, growth of lines in serum free media and analysis of specific receptors is also ongoing. Regarding the genesis of the disease, we have shown that specific types of asbestos fibers will cause human monocytes to produce TNF, IL-I, and 11-6, and that the more carcinogenic asbestos fibers will upregulate NO production in the presence of interferon. We have developed a swine model of isolated lung perfusion with tumor necrosis factor and have started a Phase I clinical trial to define the maximum tolerated dose of this therapy. A neoadjuvant trial of interferon, cisplatinum 5-FU, and leucovorin is also ongoing in which labelling index of esophageal cancer, utility of endoesophageal ultrasound, and response rates are being studied.